SummaryWhat forces direct brain organization and its plasticity? When a brain region is deprived of its input would this region reorganize based on compensation for the disability and experience, or would strong limitations of brain structure limit its plasticity? People born without hands activate their sensorimotor hand region while moving body parts used to compensate for this ability (e.g. their feet). This has been taken to suggest a neural organization based on functions, such as performing manual-like dexterous actions, rather than on body parts. Here we test the selectivity for functionally-compensatory body parts in the sensorimotor cortex of people born without hands. Despite clear compensatory foot use, the sensorimotor hand area in the dysplasic subjects showed preference for body parts whose cortical territory is close to the hand area, but which are not compensatorily used as effectors. This suggests that function-based organization, originally proposed for congenital blindness and deafness, does not apply to cases of the primary sensorimotor cortex deprivation in dysplasia. This is consistent with the idea that experience-independent functional specialization occurs at relatively high levels of representation. Indeed, increased and selective foot movement preference in the dysplasics was found in the association cortex, in the inferior parietal lobule. Furthermore, it stresses the roles of neuroanatomical constraints such as topographical proximity and connectivity in determining the functional development of brain regions. These findings reveal limitations to brain plasticity and to the role of experience in shaping the functional organization of the brain.Significance StatementWhat determines the role of brain regions, and their plasticity when typical inputs or experience is not provided? To what extent can extreme compensatory use affect brain organization? We tested the functional reorganization of the primary sensorimotor cortex hand area in people born without hands, who use their feet for every-day tasks. We found that it is preferentially activated by close-by body-parts which cannot serve as effectors, and not by the feet. In contrast, foot-selective compensatory plasticity was found in the association cortex, in an area involved in tool use. This shows limitations of compensatory plasticity and experience in modifying brain organization of early topographical cortex, as compared to association cortices where function-based organization is the driving factor.ClassificationBiological Sciences\Neuroscience